Use of docosahexanoic acid as active substance for the treatment of lipodystrophy

ABSTRACT

Use of an extract of animal, plant or microorganism produced origin comprising docosahexaenoic acid as active substance for the manufacture of a medicament for the treatment of lipodystrophy in a mammal. Said treatment is effective and overcomes the disadvantages of current lipodystrophy treatments in HIV infected patients.

FIELD OF THE INVENTION

This invention relates to the use of an extract of animal, plant ormicroorganism-produced origin comprising docosahexaenoic acid as activesubstance for the manufacture of a medicament for the treatment oflipodystrophy, particularly in patients infected by the HIV virus.

BACKGROUND OF THE INVENTION

Treatments have been available since the end of 1996 which are capableof controlling multiplication of the human immunodeficiency virus (HIV),which is the cause of acquired immune deficiency syndrome (AIDS). Thesetreatments have been generically so-called highly active anti-retroviraltherapy (HAART). The current HAART characteristically consists in thecombination of at least three drugs.

There are at present two families of antiretrovirals that inhibit keyenzymes for viral replication and which are the reverse transcriptaseinhibitors (nucleoside analogues, nucleotide analogues and nucleosidenon-analogues) and the viral protease inhibitors.

However, such treatments are not capable of leading to eradication ofthe virus (elimination thereof) and, to keep the infection controlledthey, therefore, have to be administered indefinitely, probablythroughout the patient's entire lifetime.

Such treatments, of undoubted efficacy in controlling viral replication,are nevertheless not innocuous for patients, and because the exposuretime thereto is, necessarily, very lengthy, their toxic effects tend toaccumulate over time.

Since 1997 there began to be detected patients submitted to HAART whopresented disorders not previously described in body-fat distribution,accompanied by plasma lipid level disorders.

Briefly, the patients show loss of fat in the face, buttocks,extremities and thorax, accompanied by accumulation of fat inside theabdomen, the back of the neck and in the breast area in women, togetherwith increase plasmatic levels of cholesterol, triglycerides, loweringof HDL cholesterol (protective cholesterol) and increase of LDLcholesterol (harmful cholesterol), insulin resistance (occasionallydiabetes) and occasionally arterial hypertension.

This entire set of situations is known as lipodystrophy syndrome.

Approaches to the treatment of lipodystrophy can be summed up in fivebroad groups:

(a) Strategies which modify the HAART components, so that this cannot besuppressed without running the risk of losing control over viralreplication. (b) Drugs (e.g. methformine, rosiglytazone) which causesensitisation to the action of insulin.

(c) Drugs which aim to control the lipidic aspects of the syndrome, suchas fibrates and statines, which can improve (though rarely normalise)plasmatic lipid disorders.

(d) Hormone treatments (e.g. growth hormones).

(e) Facial cosmetic surgery with implants to correct fat loss.

None of the treatments tested so far have shown any efficacy inreversing the disorders in body fat distribution, and the control oflipidic disorders using such measures has been incomplete.

It should be mentioned that the foregoing tested pharmacologicaltreatments are not without toxic effects on the patient, which can,occasionally, be serious. They furthermore, mean an additional drugburden, and some of them interact in a potentially serious way with theantiretroviral drugs which HIV-infected patients cannot stop taking.

There is still, therefore, no available treatment for lipodystrophy, inparticular in HIV-infected patients, which is effective and does notgive rise to the disadvantages of the treatments currently known.

DESCRIPTION OF THE INVENTION

The inventors of the present invention have found a treatment effectiveagainst lipodystrophy and which, furthermore, overcomes thedisadvantages presented by the current treatments for said illness inHIV-infected patients.

This invention relates to the use of an extract of animal, plant ormicroorganism-produced origin that comprises docosahexaenoic acid asactive substance for the manufacture of a medicament for the treatmentof lipodystrophy in a mammal.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid which contains 22atoms of carbon, being six of them unsaturated (C22:6 n-3). Such acid isfound, mainly, in fish (for example, tuna), microorganisms and plants.

In this invention, “extract of animal, plant or microorganism-producedorigin that comprises docosahexaenoic acid as active substance” is takento mean a composition which includes docosahexaenoic acid, which isobtained from fish, microorganisms and plants, by means of extraction,and optionally, chemical-modification procedures known to those skilledin the art.

In this invention, “microorganism” is taken to mean any microscopicorganism, including but not limited to bacteria, protozoa, fungi,viruses and algae, and any of their variants produced by geneticengineering, which are characterized in that they produce DHA.

Docosahexaenoic acid can, thus, be one occurring naturally or onemodified chemically. The chemical forms in which the DHA can be foundtherefore include, but are not restricted to, the free acid of DHA, DHAesters with natural or synthetic alcohols and lipidic forms such as theglycerides, phospholipids, sphingolipids and gangliosides.

In particular, this invention relates to the use of an extract ofanimal, plant or microorganism-produced origin that comprisesdocosahexaenoic acid as active substance for the manufacture of amedicament for the treatment of lipodystrophy in mammals, said extracthaving a DHA content that ranges between 5% and 100% (w/w), preferablybetween 50% and 100% (w/w).

Surprisingly, the inventors of the present invention have found that thefact that the DHA is a physiological substance possessing multipleactions on the adipocytes (fat cells) and on plasma lipid levels permitsthe effective treatment of lipodystrophy.

Principal among these is its ability to promote differentiation(multiplication) of the adipocytes, reduce blood triglyceride andcholesterol levels, increase HDL cholesterol level, reduce LDLcholesterol level, and reduce arterial blood pressure.

Additionally, the DHA possesses anti-inflammatory properties (itinhibits the secretion of alpha tumour necrosis factor) which, as willbe shown below, is high in patients with lipodystrophy.

In a second aspect, a dosage of the medicament of the invention isadministered equal to or higher than 100 mg/day, a dosage of 4 grams perday being preferable.

A medicament according to this invention can be administered orally orparenterally.

Depending on the chosen route of administration, pharmaceuticallyacceptable diluents, excipients and/or carriers of the active substancecan be included, such as liposomes, microemulsions, micelles, etc.

In a third aspect, the medicament of the invention is administered to ahuman, preferably an HIV-infected human.

It has been found, indeed, that administration of the medicament of theinvention in cultured adipocytes is capable of inhibiting the toxiceffects caused by the exposure of these cells to the antiretroviraldrugs.

Therefore, and taking into account the beneficial effects pointed outabove, the medicament of this invention can perform a beneficial actionon lipodystrophy syndrome, especially in HIV-infected patients treatedunder HAART regimens, having the following advantageous aspects inrelation to current treatments:

1. adipocytary differentiation promoter activity;

2. hypolipemiant activity;

3. anti-inflammatory activity (reduction of the alpha tumour necrosisfactor);

4. antihypertensive activity;

5. absence of side effects at the dosages administered;

6. absence of interactions with the antiretroviral regimen componentsdue to it being a medicament that is not metabolised by routes common tothose of the antiretroviral drugs (it should be remembered that thepatient cannot dispense with HAART).

There follows, by way of non-restrictive illustration, an example ofembodiment of this invention.

EXAMPLES Example 1

Four HIV-infected patients under HAART regimen and presentinglipodystrophy syndrome were administered 4 grams/day of a tuna oil witha DHA content of 70%. After three months' administration of DHA to saidpatients, the following discoveries were made, even taking account ofthe short period of administration:

-   -   1. Partial reversal of body-fat distribution disorders, with        -   1.1 improvement in facial fat loss;        -   1.2 improvement in fat loss in buttocks and extremities;        -   1.3 no increase in intra-abdominal fat.    -   2. Mean reduction of 56% in the plasma triglycerides number.    -   3. Mean reduction of 25% in the total plasma cholesterol number.    -   4. Mean increase of 9% in the plasma HDL cholesterol number.    -   5. Mean reduction of 18% in the plasma LDL cholesterol number.

These results, shown in the table on the following page, allow us toconclude that the administration of DHA at dosages of 4 grams a day overthe course of 3 months is capable of improving lipodystrophy and thelipidic disorders associated with it. TABLE before the treatment after 3months of treatment VLDL COL. TG HDL LDL VLDL COL. TG HDL LDL Patient 11.27 6.8 7.1 1.1 3.67 0.46 5.46 1 1.57 3.43 Patient 2 3.96 9.95 8.621.12 4.87 3.74 9.48 10.66 0.91 3.35 Patient 3 2.18 5.18 6.29 1.09 1.910.8 3.82 1.73 1.05 1.97 Patient 4 11.41 19.13 30.8 1.92 0.79 1.82 9.93.41 0.98 6.67

Example 2

From the four patients treated with DHA at elevated dosages (1.5 g/day),all of them have been monitored for 300 days and, although notablefluctuations are observed, especially regarding to the triglicerids (seeTable 2), after 300 days of monitoring, the reduction's mean in thenumber of triglycerids with respect to the basal level is 66% and forthe cholesterol is 28,0%. At the same time, the HDL cholesterol shows adrop op 11.6%.

All patients have improved their fat redistribution, from the point ofview subjective and according to the skill's criterion. TABLE 2 beforethe treatment 15 days of treatment 30 days of treatment Patient COL. TGHDL LDL VLDL COL. TG HDL LDL VLDL COL. TG HDL LDL VLDL 1 6.8 7 1.1 3.671.27 6.37 1.16 1.7 4.14 0.53 6.16 1.35 1.79 3.7 0.62 2 9.95 8.6 1.124.87 3.96 9.74 5.98 0.98 6.07 2.61 8.4 6.9 0.86 4.3 3.18 3 5.18 6.2 1.091.91 2.18 3.92 3.11 1.05 1.86 1.01 4.07 3.09 1.06 2.0 0.97 4 19.13 301.92 0.79 11.41 8.73 5.18 1.03 5.35 2.35 8.5 5.74 1.16 5.0 2.26 60 daysof treatment 120 days of treatment 180 days of treatment Patient COL. TGHDL LDL VLDL COL. TG HDL LDL VLDL COL. TG HDL LDL VLDL 1 5.46 1 1.573.43 0.46 5.49 1.45 1.56 3.26 0.67 6.15 2.63 1.56 3.38 1.21 2 9.48 10.660.91 3.35 3.74 8.24 6.36 1.08 4.6 2.56 9.64 15.75 1.04 2.3 4.38 3 3.821.73 1.05 1.97 0.8 3.47 1.51 1.16 1.61 0.7 3.76 2.87 0.94 1.5 132 4 9.93.41 0.98 6.67 1.82 13.63 31.7 0.7 1.46 9.67 13.21 16.37 1.48 2.09 3.97240 days of treatment 300 days of treatment Patient COL. TG HDL LDL VLDLCOL. TG HDL LDL VLDL 1 5.7 1.59 1.67 3.3 0.73 6.01 1.57 1.23 4.06 0.72 28.1 5.36 0.98 4.93 2.12 9.3 7.21 1.08 5.31 2.92 3 4.04 1.85 1.09 2.10.85 4.34 1.62 0.89 2.7 0.75 4 5.33 2.18 1.17 3.16 1 4.27 1.36 1.22 2.420.63

1. Use of an extract of animal, plant or microorganism-produced originthat comprises docosahexaenoic acid as active substance for themanufacture of a medicament for the treatment of lipodystrophy in amammal, said medicament being administered to a patient who isconcomitantly receiving a highly active anti-retroviral therapy (HAART).2. Use according to claim 1, wherein the amount of docosahexaenoic acidin said extract is higher than or equal to 100 mg/day.
 3. Use accordingto claim 2, wherein said amount of docosahexaenoic acid in said extractis 4 grams/day.
 4. Use according to claim 1, in which the medicamentpromotes adipocytary differentiation.
 5. Use according to claim 1, inwhich the medicament has hypolipemiant activity.
 6. Use according toclaim 1, in which the medicament reduces the alpha tumour necrosisfactor.
 7. Use according to claim 1, in which the medicament hasantihypertensive activity.
 8. Use according to claim 1, in which themedicament is capable of inhibiting the toxic effects caused by theadministration of an antiretroviral drug.
 9. Use according to claim 1,in which said docosahexaenoic acid is present in said extract in aconcentration which ranges between 5% and 100% (w/w).
 10. Use accordingto claim 9, in which said docosahexaenoic acid is present in saidextract in a concentration which ranges between 50% and 100% (w/w). 11.Use according to claim 1, in which the medicament is administeredorally.
 12. Use according to claim 1, in which the drug is administeredparenterally.
 13. Use according to claim 1, in which said mammal is ahuman.
 14. Use according to claim 13, in which said human is infectedwith the HIV virus.